Sorting nexins (SNXs)are a family of mammalian proteins that contain newly described domain termed the PX domain. Numerous SNXs also have close homology to several proteins that are required for normal protein trafficking in yeast. SNX1 and SNX2 are orthologs of Vps5p, a protein involved in retrograde traffic of proteins from late endosomes to the TGN. SNX3 is the ortholog of Grd19p, a protein required to retain proteins such as Kex2p in the Golgi. SNX8 is a close homolog of Mvp1p, a protein that interacts with a dynamin-like protein. We have obtained cDNAs for human homologs of several other components of the multimeric complex containing Vps5p (i.e., Vps26, Vps35 and Vps29. We have used yeast two hybrid assays to characterize the interactions among many of these proteins. Our data are consistent with a model in which human Vps35 serves as the core of a multimeric complex by providing binding sites for SNX1,hVps26 and hVps36. In addition, we have demonstrated that several of the SNXs interact with various receptor tyrosine kinases (e.g. receptors for EGF, PDGF and insulin), the long form of the leptin receptors, and various serine/threonine kinases (e.g. receptors for TGFbeta and activin). Recent functional studies have demonstrated that SNX15 plays a crucial role in trafficking through the endocytic pathway. Further studies are underway to elucidate the roles of the other sorting nexins and their associated proteins in intracellular protein trafficking in mammalian cells.